EXCEED THE SPACE PROVIDED. Excess liver fibrosis leads to end-stage cirrhosis with high morbidity and mortality. Presently, no effective treatment is available. The objectives of the proposed research are to establish dilinoleoylphosphatidylcholine (DLPC) as an effective, safe, and chemically defined therapeutic agent, clarify its mode of action and codify its proper use. We previously observed that polyenylphosphatidylcholine (PPC) extracted from soybeans fully prevents alcohol-induced cirrhosis in non-human primates. DLPC is the main phospholipid species of PPC and some of our prior hi vitro and current in vivo studies suggest that it is its active component. We now plan to extend these experiments, including in vitro studies of the effect of DLPC on oxidative stress in Kupffer cells, with possible involvement of cytokines as mediators between these cells, hepatocytes and stellate cells. Furthermore, economical and sufficiently pure DLPC has now become available to allow us to carry out experiments in vivo to determine whether the beneficial effects of PPC in terms of steatosis and fibrosis can be reproduced with DLPC. The mechanisms of the prevention of apoptosis will also be investigated. In addition, we will assess whether DLPC can reverse preexisting fibrosis, either produced by CCH or heterologous albumin in the rat or by alcohol in our baboon model. Currently one of the rate limiting factors of the therapeutic use of PPC is the dose (3 daily 3.3 gm tablets). Theoretically, if DLPC is confirmed to be the active compound, it could be given at a much higher dose, at least twice that of PPC. Therefore, we will test whether an effect on liver fibrosis greater than that of PPC could be achieved with a higher dose of DLPC. We will also attempt to boost the effect of DLPC by combining it with the non-toxic activated ammo-acid S-adenosyhnethionine, since both compounds act on different, but interdependent, steps required for an effective defense against the oxidative stress caused by ethanol and also for the maintenance of the normal structure and function of cellular membranes. If the proposed approach is successful, it may provide the preclinical studies needed to plan a multicenter, placebo controlled clinical trial to define the effectiveness of the SAMe + DLPC combination for the prevention of alcoholic liver disease and its treatment in man.